Stressful life events are thought to precipitate depressive episodes in vulnerable individuals. There appears to be a biochemical link between stress and depression since dysregulation of the stress-responsive hypothalamic-pituitary-adrenal (HPA) axis, manifested in cortisol hypersecretion, frequently occurs in melancholic depressed patients, and remission from depression leads to normalization of this dysregulation. Inversely, decreasing the levels and efficacy of glucocorticoids can ameliorate symptoms of depression. Thus, there is clinical evidence that hypercortisolemia may be associated with the pathophysiology of a subtype of depression.
Synthesis and secretion of glucocorticoids is regulated by ACTH which in turn is primarily stimulated by the hypothalamic corticotropin releasing factor (CRF). CRF appears to mediate not only the endocrine, but also the autonomic and behavioral responses to stress, the later event occurring directly in the brain. Increased production of CRF is thought to be involved in the etiology of depression. Thus, CRF receptor antagonists have been developed and tested for their anxiolytic and antidepressant characteristics.
Recently studies demonstrated that prepro-TRH 178-199, a peptide derived from the TRH precursor, inhibits ACTH secretion in vitro (Redei et al., 1995, Endocrinology 136:1813-1816; Redei et al., 1995, Endocrinology 136:3557-3563) and plasma ACTH, CORT, and prolactin responses to stressors in vivo (McGivern et al., 1997, J. Neurosci. 17:4886-4894). It has also been reported that centrally administered prepro-TRH 178-199 produced behavioral effects in rats in paradigms used to assess response to novelty and anxiolytic potential (McGivern et al., 1997, J. Neurosci. 17:4886-4894). Intracerebroventricular (i.c.v.) administration of prepro-TRH 178-199 into the lateral ventricle induced significant increases of locomotion in the open field test of time spent in the open arms of the elevated plus maze and in the light compartment of the light/dark box. Thus, prepro-TRH 178-199, administered directly into the brain, increases arousal and exploratory behavior, and decreases anxiety in experimental paradigms routinely used to assess these behaviors in animals.
Currently, while anti-depressive therapeutic compounds are available, each of these compounds may have deleterious side effects. There is therefore a need in the art for the discovery and development of additional compounds which alleviate depression. The present invention satisfies this need.
The invention relates to a method of treating a depressive disorder in an animal. The method comprises administering to said animal a compound having CRIF biological activity.
In one aspect, the compound is a peptide.
In another aspect, the compound is a peptidometic.
In yet another aspect, the compound is in a therapeutically effective amount.
In a further aspect, the compound is in a pharmaceutically acceptable carrier.
In yet another aspect, the animal is a human.
In another aspect, the compound is administered to the animal by a route selected from the group consisting of oral, parenteral, intranasal and central.
In one embodiment, the peptide is a CRIF peptide comprising at least three amino acids positioned between the fourth and fifth TRH peptide on a prepro-TRH molecule.
In a further embodiment, the CRIF peptide comprises from three to twenty two amino acids positioned between the fourth and fifth TRH peptide on a prepro-TRH molecule.
In another embodiment, the CRIF peptide comprises the sequence Phe-Ile-Asp-Pro-Glu-Leu-Gln-Arg-Ser-Trp-Glu-Glu-Lys-Glu-Gly-Glu-Gly-Val-Leu-Met-Pro-Glu (SEQ ID NO:1).
In yet another embodiment, the CRIF peptide comprises the sequence Phe-Ile-Asp-Pro-Glu-Leu-Gln-Arg-Ser-Trp-Glu-Glu-Thr-Glu-Gly-Glu-Glu-Gly-Gly-Leu-Met-Pro-Glu (SEQ ID NO:2).
In another embodiment, the CRIF peptide comprises the sequence Glu-Gly-Glu-Gly-Val-Leu-Met-Pro-Glu (SEQ ID NO:3).
In a further embodiment, the CRIF peptide comprises the sequence Leu-Met-Pro-Glu (SEQ ID NO:4).
In yet another embodiment, the CRIF peptide comprises from three to twenty six amino acids positioned between the fourth and fifth TRH peptide on a prepro-TRH molecule.
In another embodiment, the CRIF peptide comprises the sequence Leu-Ala-Asp-Pro Lys-Ala-Gln-Arg-Ser-Trp-Glu-Glu-Glu-Glu-Glu-Glu-Glu-Glu-Arg-Glu-Glu-Asp-Leu-Met-Pro-Glu (SEQ ID NO:5).
In a further aspect, the depressive disorder is selected from the group consisting of major depression, minor depression, bipolar disorders, disthymia, cyclothymia, and premenstrual syndrome.